The overall goal of this renewal application for a Midcareer Investigator Award in Patient-Oriented Research is to enable Dr. Ware to continue to build and expand her research and mentoring programs in patient-oriented research in ARDS. This award will allow her to continue to devote significant protected time to her current mentees as well as to expand her mentoring to include new postdoctoral trainees and medical students. In addition, the support of this award will allow Dr. Ware to expand the reach of her mentoring to include new efforts to enhance the mentoring skills of her mentees in order to assure strong mentoring for future generation of patient-oriented researchers. In addition, Dr. Ware's program in patient-oriented research will be expanded in new and novel directions. Specifically, she will focus on how release of cell-free hemoglobin, and genetic heterogeneity in haptoglobin, the primary endogenous scavenger of cell-free hemoglobin, determine the effects of cell-free hemoglobin on primary graft dysfunction, a form of ARDS, after lung transplantation. These studies are based on compelling preliminary data demonstrating that elevated pre-operative plasma levels of cell-free hemoglobin are strongly associated with development of primary graft dysfunction in lung transplant recipients and that the haptoglobin 2:2 genotype is associated with development of ARDS in severe sepsis. There are three specific aims. Aim 1 will test the hypothesis that plasma cell-free hemoglobin levels are associated with risk of PGD in patients undergoing lung transplantation and that this relationship is modified by FiO2 at reperfusion. Aim 2 will test the hypothesis that recipient haptoglobin 2:2 genotype is associated with a higher incidence of PGD after lung transplantation and that this relationship is modified by cell-free hemoglobin levels. Finally, Aim 3 will determine the mechanism by which cell-free hemoglobin potentiates the risk of primary graft dysfunction by quantifying biomarkers of lipid peroxidation, endothelial and lung epithelial injury and inflammation and testing their associations with pre- and post-operative cell-free hemoglobin levels and haptoglobin 2:2 genotype. These studies will lead to a better understanding of the influence of cell-free hemoglobin and haptoglobin genotypes on risk of primary graft dysfunction and may lead to improved donor selection criteria and donor-recipient matching. In addition, these studies may lead to new treatments for prevention and treatment of both primary graft dysfunction and non-transplant associated ARDS.